Synthesis and Biological Evaluation of a Fluorine-18 Derivative of Dasatinib

Veach, Darren R.; Namavari, Mohammad; Pillarsetty, Nagavarakishore; Santos, Elmer; Beresten-Kochetkov, Tatiana; Lambek, Caryl; Punzalan, Blesida; Antczak, Christophe; Smith‐Jones, Peter; Djaballah, Hakim; Clarkson, Bayard; Larson, Steven M.

doi:10.1021/jm070342g

Cited by 35 publications

(38 citation statements)

References 32 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We believe that in the future, many of these drugs will be labeled and used as probes, to show specificity of targeting in individual tumors. Present examples include F-dasatinib (for bcr/abl, src tyrosine kinase inhibitors) (Veach et al, 2007); 124 I-PUH71 (for HSP90) (Moulick et al, 2011); F(ab 0 )2-trastuzumab-Ga-68 (for HER2) (Smith-Jones et al, 2004); and 18 F-imatinib (for bcr/abl) (Glekas et al, 2011). In addition, molecular imaging of high affinity receptors such as estrogen or androgen receptors can be used to show inhibition of the target by estrogen and androgen receptor inhibitor drugs.…”

Section: Molecular Imaging In Drug Developmentmentioning

confidence: 99%

Molecular imaging for personalized cancer care

2012

Self Cite

View full text Add to dashboard Cite

Molecular imaging is rapidly gaining recognition as a tool with the capacity to improve every facet of cancer care. Molecular imaging in oncology can be defined as in vivo characterization and measurement of the key biomolecules and molecularly based events that are fundamental to the malignant state. This article outlines the basic principles of molecular imaging as applied in oncology with both established and emerging techniques. It provides examples of the advantages that current molecular imaging techniques offer for improving clinical cancer care as well as drug development. It also discusses the importance of molecular imaging for the emerging field of theranostics and offers a vision of how molecular imaging may one day be integrated with other diagnostic techniques to dramatically increase the efficiency and effectiveness of cancer care.

show abstract

Section: Molecular Imaging In Drug Developmentmentioning

confidence: 99%

Molecular imaging for personalized cancer care

2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…2C). The IC 50 , of [ 19 F]- 1 , 46 ± 30 nM, is similar but inferior to unmodified dasatinib 19 ± 20 nM and derivatives (18) (19,23), but more effective than doxorubicin (control) 710 ± 120 nM. Having verified that the imaging modifications on [ 19 F]- 1 do not greatly alter effectiveness and mechanism of action in vitro , animal studies were conducted to evaluate in vivo CED distribution.…”

Section: Resultsmentioning

confidence: 99%

“…Many recognize this and report 18 F-labeled dasatinib derivatives for stand-alone PET imaging (19–21). In addition, dasatinib is of interest for the treatment of diffuse intrinsic pontine glioma (DIPG) (5,22).…”

Section: Introductionmentioning

confidence: 99%

A Murine Model for Quantitative, Real-Time Evaluation of Convection-Enhanced Delivery (RT-CED) Using an 18[F]-Positron Emitting, Fluorescent Derivative of Dasatinib

Wang

Kommidi

Tosi

et al. 2017

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The blood brain barrier can limit the efficacy of systemically delivered drugs in treating neurological malignancies; therefore, alternate routes of drug administration must be considered. The Abl-kinase inhibitor, dasatinib, is modified to give compound 1 ([18F]-1) so that 18F-positron emission tomography (PET) and fluorescent imaging can both be used to observe drug delivery to murine orthotopic glioma. In vitro western blotting, binding studies (IC50 = 22 ± 5 nM), and cell viability assays (IC50 = 46 ± 30 nM) confirm nanomolar, in vitro effectiveness of [18F]-1, a dasatinib derivative that is visible by 18F-PET and fluorescence. [18F]-1 is used to image dynamic direct drug delivery via two different drug delivery techniques to orthotopic murine brainstem glioma (mBSG) bearing mice. Convection enhanced delivery (CED) delivers higher concentrations of drug to glioma-containing volumes vs. systemic, tail-vein delivery. Accurate delivery and clearance data pertaining to dasatinib are observed, providing personalized information that is important in dosimetry and redosing. Cases of missed drug delivery are immediately recognized by PET/CT, allowing for prompt intervention in the case of missed delivery.

show abstract

“…Originally, it was assumed that an ethyl group (substituted by a good leaving group) could be attached to the piperazine and that eventually the leaving group could be displaced with 18 F. However, because of the disappointing results of our initial attempts at this approach, the focus of the synthesis shifted to a 2-step approach: first, a 2-carbon synthon was radiolabeled with 18 F, and second, this was used as an alkylating agent with the piperazinyl nitrogen (15). The overall isolated yields of the final product were 8.9% ± 3.8% (decay-corrected, n = 11, 3.7%–14.3%) with greater than 98% radiochemical purity.…”

Section: Resultsmentioning

confidence: 99%

In Vivo Imaging of Bcr-Abl Overexpressing Tumors with a Radiolabeled Imatinib Analog as an Imaging Surrogate for Imatinib

Glekas¹,

Pillarsetty²,

Punzalan³

et al. 2011

J Nucl Med

Self Cite

View full text Add to dashboard Cite

Imatinib mesylate is a tyrosine kinase inhibitor that was approved by the U.S. Food and Drug Administration in 2001 for treatment of many different stages of chronic myeloid leukemia and in 2002 for treatment of gastrointestinal stromal tumors. Imatinib is known to inhibit the dysregulated proliferation of chronic myeloid leukemia, which is associated with the Bcr-Abl kinase; in gastrointestinal stromal tumors, imatinib is known to act via c-Kit kinase inhibition. The objective of this study was to synthesize an 18F-labeled analog of imatinib not as a primary imaging agent but rather as a tracer for in vivo drug distribution and tracer concentration that can be used as a PET imaging surrogate for imatinib. Methods Molecular modeling studies based on the crystal structure of imatinib bound to the active site of Abl were performed for designing the fluorinated analog. A 2-fluoroethyl analog of imatinib (SKI696) was synthesized using well-established procedures. The selectivity and binding affinity of SKI696 were compared with those of imatinib in vitro. Mice bearing K562 tumor xenografts, which are known to overexpress Bcr-Abl, were imaged with 18F-SKI696 PET. A biodistribution study was also performed on K562 tumor–bearing mice to which our radiolabeled tracer was administered. Results The kinase assay verified that imatinib and SKI696 bind to the same targets with similar affinities. The feasibility of using 18F-SKI696 as a PET agent was examined in vivo, and 18F-SKI696 PET was shown to visualize K562 tumor xenografts in nude mice. The tumor was visible on PET 1 h after injection, with uptake of 1% of the injected dose. Biodistribution studies in K562-bearing mice were also performed, and the uptake of 18F-SKI696 (percentage injected dose per gram) for each organ was calculated. Conclusion The results of the binding assay showed that SKI696 has selectivity and binding affinity comparable to imatinib. Small-animal PET of K562 tumor–bearing mice using 18F-SKI696 as a PET agent displayed promising tumor uptake and tumor-to-nontarget contrast. Because 18F-SKI696 has been taken up in vivo by tumors that overexpress Bcr-Abl, we are exploring a possible role for identifying tumors that will respond to imatinib before therapy.

show abstract

Synthesis and Biological Evaluation of a Fluorine-18 Derivative of Dasatinib

Cited by 35 publications

References 32 publications

Molecular imaging for personalized cancer care

Molecular imaging for personalized cancer care

A Murine Model for Quantitative, Real-Time Evaluation of Convection-Enhanced Delivery (RT-CED) Using an 18[F]-Positron Emitting, Fluorescent Derivative of Dasatinib

In Vivo Imaging of Bcr-Abl Overexpressing Tumors with a Radiolabeled Imatinib Analog as an Imaging Surrogate for Imatinib

Contact Info

Product

Resources

About